High lipid, low dextrose parenteral nutrition allows patient to achieve nutritional autonomy: A case report

Introduction Prolonged use of parenteral nutrition can eventually lead to liver abnormalities. Causative factors include decreased enteral stimulation, high intakes of intravenous dextrose, proinflammatory 100 % soybean oil-based lipids, and increased burden on liver through 24-h infusions. We present a case report of a patient who received parenteral nutrition modifications to address liver dysfunction. Presentation of case Our patient was a 37-year-old African American male with a past medical history including refractory Crohn's disease complicated by multiple small bowel obstructions, several bowel surgeries, left lower quadrant colostomy placement, short bowel syndrome, severe protein calorie malnutrition, parenteral nutrition dependence, and elevated liver function tests. He was admitted for nutritional optimization before a planned takedown of multiple chronic enterocutaneous and perianal fistulas. His home parenteral nutrition order contained high amounts of dextrose (69 % kcal), and low amounts of 100 % soybean oil (11 % kcal). Discussion Due to an elevated alkaline phosphatase level at baseline (1746 U/L), the Registered Dietitian maximized protein, decreased the dextrose by 62.5 %, and changed to SMOFlipid (a fish-oil containing lipid) at >1 g/kg/day to address liver abnormalities. Within 1.5 months of changing parenteral nutrition to high SMOFlipid (>30 % kcal) with low dextrose (<30 % kcal) content, alkaline phosphatase levels declined by 62 %, prealbumin levels increased by 56 %, and c-reactive protein levels decreased by 62 %. Conclusion Parenteral nutrition modifications led to reversal of chronic liver dysfunction. This patient ultimately underwent a successful high-risk fistula takedown procedure, allowing for complete weaning of parenteral nutrition and achievement of sustained nutritional autonomy.


Introduction
Intestinal failure associated liver disease (IFALD) is a multifactorial condition characterized by cholestasis, hepatic steatosis, and fibrosis related to parenteral nutrition (PN) use [1]. The longer a patient receives PN, the more likely they are to develop IFALD [2]. IFALD may have a variety of causative factors including decreased enteral stimulation (can lead to bile acid accumulation in the liver), 100 % soybean oil injectable lipid emulsion (SO-ILE) (contain pro-inflammatory omega-6 long chain fatty acids and phytosterols), high amounts of dextrose (can increase insulin secretion and stimulate lipogenesis leading to hepatic fat accumulation), and 24-h PN infusions (can be an increased burden on the liver via constant processing of intravenous calories) [1,3,4].
Nutrition interventions are typically the first line therapy to address IFALD (e.g., reducing the infusion time of PN, reducing calorie targets, decreasing dextrose content, and limiting SO-ILE to reduce the infusion's burden on the liver) [1,3,4]. High amounts of calories from dextrose specifically have been linked to liver abnormalities in long term home PN patients [2,5,6]. To minimize risk of dextrose and SO-ILE via PN, recommendations include prescribing dextrose <65 % total kcal, limiting dextrose to <4 g/kg/day, maintaining a glucose infusion rate of <4 mg/kg/min, and dosing SO-ILE <1 g/kg/day [1,2,4,7]. However, Abbreviations: ALP, alkaline phosphatase; BMI, body mass index; CRP, c-reactive protein; IFALD, intestinal failure associated liver disease; LFT, liver function test; PAB, prealbumin; PN, parenteral nutrition; SBS, short bowel syndrome; SO-ILE, 100 % soybean oil intravenous lipid emulsion. utilizing a combination of these nutrition strategies increases the risk of underfeeding. Newer generation lipids containing fish oil can assist with optimizing non-dextrose calories in PN and ameliorate the proinflammatory effects of SO-ILE [8]. SMOFlipid® (Fresenius Kabi) is a mixed lipid emulsion containing 30 % soybean oil, 30 % medium-chain triglycerides, 25 % olive oil, and 15 % fish oil [9]. We present a retrospective case report of a patient who received higher doses of SMOFlipid to address IFALD which resulted in successful surgical intervention, complete weaning of PN, and achievement of nutritional autonomy. This patient was managed at an acute care, inpatient, academic, tertiary referral hospital in the United States. This case was reported in line with SCARE criteria [10].

Case presentation
The patient discussed in this report is a 37-year-old African American male with a body mass index (BMI) of 18.6 and a past medical history including refractory Crohn's disease complicated by multiple small bowel obstructions, several bowel surgeries, left lower quadrant colostomy placement, short bowel syndrome (SBS), severe protein calorie malnutrition, PN dependence, and elevated liver function tests (LFTs). He is an ambulatory non-smoker without alcohol or illicit drug use and only has a family history of paternal hypertension. He initiated PN in May 2019, began to have elevated alkaline phosphatase (ALP) levels >200 U/L in July 2019, and sustained ALP levels >1000 U/L since June 2020. He presented to our facility in October 2021 for nutritional optimization before a planned takedown of chronic lower abdominal enterocutaneous fistulas (x3) and a perianal fistula.
His baseline ALP level upon admission was 1746 U/L. This patient also had significant challenges maintaining central venous access, as his only access site was a femoral line. Prior to admission, pre-intervention measures taken to reduce the inflammatory burden on the liver was to decrease the dose of SO-ILE and condense the PN infusion time to 12 h. However, due to elevated nutrition needs for multiple fistulas and severe malnutrition, more calories from dextrose were provided to compensate for reduction of SO-ILE, and the infusion was transitioned back to 24 h to replace fistula losses. His home PN order provided an average of 33.5 kcal/kg with 69 % of calories from dextrose and only 11 % of calories from SO-ILE (Table 1).
There was no delay from presentation to intervention, and the primary type of intervention strategy was nutritional via modification of PN composition. Other peri-interventional strategies included vitamin D supplementation for a baseline deficiency (12.8 ng/dL) and initiation of 3 weeks of ursodeoxycholic acid by the hepatology team. Pertinent medication use throughout admission is outlined for review (Table 2).
Upon admission to our facility for nutrition optimization, the Registered Dietitian increased the protein to the maximum level tolerated (2.7 g/kg, 37 % kcal), decreased the dextrose by 62.5 %, and changed the SO-ILE to SMOFlipid with a goal of >1 g/kg/day as a total nutrient admixture (amino acids, dextrose, and lipids in the same bag) ( Table 1). For the first 22 days, TPN was provided as a 24-h infusion to replenish fistula losses. However, on day 23 the infusion was transitioned to cyclic over 12 h to allow for liver rest. To ensure consistency in administration, the patient received PN and lipids daily throughout admission.
Over 44 days (about 1.5 months), ALP levels decreased by about 62 % from 1746 U/L to 659 U/L (Fig. 1). Prealbumin (PAB) levels increased by about 56 %, and c-reactive protein (CRP) levels decreased by about 62 % (Fig. 2). Vitamin D levels also increased by about 71 % (Fig. 3). There were no complications or adverse/unanticipated events, and the patient tolerated treatment without laboratory abnormalities. Serum triglyceride levels peaked at 115, renal function remained within normal limits, normoglycemia was maintained throughout admission with no episodes of hyperglycemia (>180 mg/dL) or hypoglycemia (<70 mg/ dL), and body weight remained stable.

Discussion
A variety of management approaches are typically needed to address the liver dysfunction associated with IFALD. Medically, the patient can be given hepatoprotective agents (e.g., ursodeoxycholic acid) to improve bile flow/inflammation and antibiotics (e.g., metronidazole) to assist with intestinal overgrowth of anaerobic bacteria that can lead to elevated LFTs [11,12]. Nutritionally, fish oil-based lipid emulsions containing omega-3 fatty acids may assist with improving LFTs by reducing liver inflammation, improving insulin resistance, and decreasing lipid accumulation in the liver [1,8,[13][14][15]. There are other completely plant-based mixed oils available to reduce omega-6 fatty acid and phytosterol intake, however SMOFlipid has the lowest phytosterol content and the highest amount of omega-3 fatty acids comparatively [8].
Serum PAB was used as a surgical marker to evaluate the likelihood of improved surgical outcomes in this high-risk SBS patient [16]. PAB is primarily synthesized in the liver and is a negative acute-phase reactant (tends to decrease with inflammation), while CRP levels tend to increase  with inflammation [16]. Therefore, a variety of nutritional strategies were utilized to focus on correction of LFTs and decreasing inflammatory components of PN (e.g., decreasing dextrose, increasing protein, addition of fish oil, encouragement of oral intake despite malabsorptive component of SBS, cycling the PN) in order to indirectly optimize PAB and CRP levels to prepare for surgery. Our analysis has both strengths and limitations. The primary strength of this descriptive analysis is the time in which reversal of 2.25 years of IFALD began to occur using SMOFlipid (44 days). Using higher doses of SMOFlipid allowed us to meet our patient's elevated calorie needs (30 kcal/kg) while simultaneously addressing liver abnormalities. Although all potential LFT confounders were unable to be completely mitigated (e.g., oral intake, cyclic PN, antibiotics, gallstone dissolvents), we feel the primary intervention was modification of PN lipid and dextrose content. Our patient was on a solid oral diet prior to admission, so the degree of enteral stimulation was not different at baseline. Furthermore, cyclic PN prior to admission did not lead to improvements in LFTs. Moreover, if our patient's home PN order was made cyclic over 12 h to allow for liver rest, the glucose infusion rate would have exceeded 9.4 mg/kg/min, which is not recommended [2,7]. Additionally, metronidazole (the antibiotic provided to assist with IFALD) was not specifically prescribed [12].
Dosing guidelines for SMOFlipid are 1-2 g/kg/day [9], so applying these dosing guidelines are within manufacturer's recommendations and unlikely to pose risk if applied to a larger population. The novelty of our technique was utilizing higher doses of SMOFlipid (>1 g/kg/day, >30 % kcal) and protein (>35 % kcal) to achieve a lower dextrose solution (<30 %). A learning curve may occur for clinicians when dosing mixed lipids >1 g/kg since SO-ILE has been historically dosed minimally to prevent complications. Regarding cost, a recent international analysis showed sizable financial savings associated with fish oil containing lipids [17]. The key takeaway of our analysis shows that using higher doses of SMOFlipid and protein to minimize the complications of overfeeding dextrose can help patients prevent/treat liver abnormalities while also achieving calorie targets.

Conclusion
Prior to presentation, our patient had a 2.25-year history of liver abnormalities related to PN. Within 1.5 months of PN formulation changes, ALP levels declined by 62 %, PAB levels increased by 56 %, and CRP levels decreased by 62 %, allowing this patient to undergo a highrisk fistula takedown procedure successfully. With much gratitude our patient discontinued long term PN dependence and transitioned to meeting his nutrition needs via oral diet alone, which has continued to the present day at multiple follow up clinic appointments (e.g., 6-month, 12-month, 18-month).
In combination with classic recommendations to address liver dysfunction in patients on PN, newer generation lipids containing fish oil (specifically SMOFlipid) may allow patients to achieve higher calorie targets while preventing/treating liver abnormalities. Using higher doses of SMOFlipid (>1 g/kg, >30 % kcal) and protein in PN to provide lower amounts of dextrose (<30 % kcal) is an area that warrants exploration in future randomized control trials.

CRediT authorship contribution statement
Writing the paper, Study Concept: Andrew Adorno, Jennifer Silinsky, Michael Ghio, Nathaniel Rogers, John Tyler Simpson, Chrissy Guidry.
Data collection, Study Concept: Andrew Adorno, Michael Ghio, Nathaniel Rogers, John Tyler Simpson.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval
Ethical approval for this study (2021-181) was provided by an Institutional and Ethics Review Board in New Orleans, Louisiana, United States on 3 May 2021.

Consent
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.